Study of HLA-Haploidentical Stem Cell Transplantation to Treat Clinically Aggressive Sickle Cell Disease

A Phase II Study of HLA-Haploidentical Stem Cell Transplantation to Treat Clinically Aggressive Sickle Cell Disease

The study is a Phase II clinical trial. Patients will receive intensity modulated total body irradiation (TBI) at a dose of 3 Gy with standard fludarabine/ i.v. cyclophosphamide conditioning prior to human leukocyte antigen (HLA)-haploidentical hematopoietic stem cell transplant (HSCT).

The primary objective of the study is to determine the engraftment at Day +60 following HLA-haploidentical hematopoietic stem cell transplant protocol using immunosuppressive agents and low-dose total body irradiation (TBI) for conditioning and post-transplant cyclophosphamide in patients with sickle cell disease.

Patient Eligibility:

1. Patients with sickle cell disease are eligible if they have any of the following complications:

   1.1 Stroke or central nervous system event lasting longer than 24 hours 1.2 Frequent vaso-occlusive pain episodes, defined as ≥ 3 per year requiring emergency room, acute care center, hospital admissions, or home bedrest leading to absence from work or school. 1.3 Recurrent episodes of priapism, defined as ≥ 2 per year requiring emergency room visits 1.4 Acute chest syndrome with recurrent hospitalizations, defined as ≥ 2 lifetime events 1.5 Red-cell alloimmunization (≥ 2 antibodies) during long-term transfusion therapy 1.6 Bilateral proliferative retinopathy with major visual impairment in at least one eye 1.7 Osteonecrosis of 2 or more joints 1.8 Sickle cell nephropathy, defined by a GFR < 90mL/min/1.73m2 or the presence of macroalbuminuria (urine albumin > 300 mg/g creatinine) 1.9 Pulmonary hypertension, defined by a mean pulmonary arterypressure >25mmHg

2. Age 16-60 years

3. Karnofsky performance status of 60 or higher (Appendix A)

4. Adequate cardiac function, defined as left ventricular ejection fraction ≥ 40%

5. Adequate pulmonary function, defined as diffusion lung capacity of carbon monoxide ≥ 50% predicted (after adjustment for hemoglobin concentration)

6. Estimated GFR ≥ 50mL/min/1.73m2 as calculated by the modified MDRD equation

7. ALT ≤ 3x upper limit of normal

8. HIV-negative

9. Patient is not pregnant

10. Patient is able and willing to sign informed consent

11. Patient does not have a fully HLA-matched sibling donor

12. Patient has an HLA-haploidentical relative

Donor Eligibility Relatives (parents, offspring, siblings, aunts/uncles, cousins) will be tested by molecular typing of HLA class I (A, B, and C) and class II (DRB1) at low resolution. Only those that are an HLA-haploidentical match (≥ 4/8) will be considered as a potential donor. NOTE: If during testing, a fully HLA-matched sibling donor is found and is willing to donate his/her stem cells, the potential subject will not be eligible for this protocol.

Donor consent will be obtained as per standard protocol of the bone marrow transplant unit.